PROJECT SUMMARY Obstructive sleep apnea (OSA) is a common disorder that impairs stable breathing during sleep. OSA is a risk factor for type 2 diabetes, a leading cause of worldwide disability and cardiovascular disease. Furthermore, OSA can induce insulin resistance, vascular dysfunction, and inflammation ? insults that ultimately lead to diabetes and atherosclerotic cardiovascular disease. Currently, the mechanism by which OSA causes cardiometabolic dysfunction is not known. This lack of knowledge makes it impossible to determine which asymptomatic patients require treatment, or to salvage the metabolic health of those unable to tolerate continuous positive airway pressure (CPAP) therapy. Intermittent hypoxia (IH) has been used to simulate a OSA in mice. Chronic IH has been shown to cause dyslipidemia, vascular stiffness, and glucose intolerance. Moreover, acute IH increased plasma free fatty acids (FFA) and hyperglycemia in a dose- dependent manner, and these effects were abolished by pharmacologic or surgical interruption of the sympathetic nervous system. Recently, it has also been shown that OSA increases nocturnal FFA and glucose levels and causes insulin resistance during sleep. These findings demonstrate that OSA is a potent episodic cause of adipose tissue lipolysis and inhibited glucose clearance, with potentially devastating cumulative long-term impacts. The goal of this project is to understand: (Aim 1) in which OSA patients do FFA and glucose elevations occur, and (Aim 2) by what mechanism? Answers to these questions will identify susceptible patients with OSA, and identify treatment targets for these individuals. It is hypothesized that severity of OSA (as measured by AHI or by increased median heart rate during sleep) correlates with substrate elevations. Additionally, independent and/or interactive effects of gender and AHI on metabolism will be assessed. In a mouse model of IH, beta adrenergic blockade with propranolol prevented metabolic dysfunction. Thus, the second aim of this project is to test the efficacy of propranolol versus placebo in human OSA for preventing nocturnal substrate elevations. This proposal will discover mechanisms by which OSA contributes to metabolic dysfunction, identify patients susceptible to this pathophysiology, and introduce the novel use of beta blockade for therapy.